Malignant transformation is characterized by uncoupling of proliferation and differentiation, leading to continuing amplification of cells with loss of their ability to progress to differentiation. Agents capable of restoring the differentiation ability of cancer cells are thus potentially useful in cancer therapy.
Various extracts, proteins and chemicals have been shown to induce differentiation of certain cancer cells in vitro and in vivo. For example, Sachs et al. (1987) Cancer Research 47: 1981 provide a review of induction of differentiation of leukemia myeloid hematopoietic cells, including observations that myeloid leukemia cells can be induced to differentiate in vitro and in vivo by a normal differentiating protein. Tallman et al. (1992) J. Clin. Pharmacol. 32: 868 review the role of retinoids in cancer treatment. Retinoids have been investigated as differentiating agents for the prevention and therapy of bladder and mammary cancers and leukemias. Platica et al. (1992) Endocrinology 131: 2573 report that extracts of bovine pituitary and a rat mammosomatotropic tumor induce differentiation of rat mammary tumor cells.
Differentiation agents identified by in vitro studies and in vivo rodent studies have also been assessed clinically. For example, differentiation agents including hexamethylene bisacetamide and retinoic acid have entered clinical trials for cancer treatment and prevention and are reviewed by Linskey et al. (1995) Neurosurgery 36: 1. Successful use of differentiation agents for the treatment of acute promyelocytic leukemia has been reported by Warrell et al. (1993) New Engl. J. Med. 329: 177. Retinoids have been shown to be therapeutically useful in the treatment of cervical cancer by Lippman et al. (1993) J. Natl. Cancer Inst. 85: 499.
The clinical use of differentiation agents to induce cancer cells to differentiate and thus assume more normal characteristics has been termed differentiation therapy. Differentiation therapy provides an alternative approach to conventional cancer therapy such as cytotoxic chemotherapy. Accordingly, there is a need in the art for the identification and isolation or synthesis of new agents capable of promoting the differentiation of cancer cells.